Therapeutic embolization is the intentional endovascular occlusion of a mammalian artery or vein. Historically, the first agent used for embolotherapy was autologous blood clot. This was easily and quickly obtained and was inherently biocompatible. The drawback of autologous blood clot is that as the body's natural clot lysis dramatically limits the durability of occlusion; recanalization can recur within hours to days. The next agents developed were fascial strips harvested from dura and tensor fascia lata. Silk threads were also historically used as embolic agents, notably for intracranial vascular malformations, however, with the advent of modern liquid and particulates, silk, clot, and fascia are no longer commonly used.
Numerous embolic materials and devices have been described during the last 40 years. Modern embolic agents are either temporary or permanent. Permanent agents are more common, and there are many applicable subsets including liquid agents, particulates, coils, detachable plugs and balloons.
Use of mechanical embolic devices such as detachable embolic coils and balloons are well known in the art. Embolic coils are typically used for occlusion of larger vessels and cause complete occlusion equivalent to surgical ligation. Coils cause vessel occlusion by inducing thrombosis. Deployment of a coil acts by physically slowing or stopping blood flow, providing a thrombogenic surface for clot formation, and causing vessel wall damage that results in release of thrombogenic factors. Bare coils can only partially embolize vessels by pure mechanical occlusion. Because coil embolization depends on the ability of the patient to form thrombus, coagulopathic states such as thrombocytopenia, platelet dysfunction, and abnormal clotting factors may hinder complete vessel occlusion. Time to occlusion also depends on the type of coil used, as well as the rate of flow of the target vessel embolized. Certain detachable embolic coils are electrolytically detachable (see Guglielmi et al. J Neurosurg 1991; 75:11-17), while others, known as hydrogel coils are detachable platinum coils coated with an expandable polymer (see Kallmes et al. Am J Neuroradiol 2002; 23(9):1580-1588). Another published article (AJNR: 6, July/August 1985) describes the use of detachable coils and balloons in conjunction with embolization procedures in polyvinyl alcohol (PVA) sponge, gelatin sponge, or isobutyl-2 cyanoacrylate (IBCA).
Various forms of gelatin foam have been used as an intravascular embolization agent for more than 30 years, with the first intravascular use in 1964 for cavernous carotid fistulas (J Neurosurg 1964; 21: 303-315). Since that time, gelatin foam has evolved into a common agent used for a variety of applications. Gelatin foam is a biologic substance made from purified skin gelatin. It is commonly available as Gelfoam® from Pharmacia and Upjohn Co (division of Pfizer Inc. New, York, N.Y.) in sterile sheets and as a powder comprised of 40 to 60 mm particles. Sheets can be cut into a variety of shapes. Gelfoam® cut into small 1 to 2 mm pieces can be mixed with dilute contrast and injected as pledgets, or be prepared as slurry. Another embolic use of gelatin foam is to form a small torpedo that can be injected into the target vessel for a more proximal occlusion. Gelatin foam causes mechanical obstruction, slowing blood flow and hastening thrombus formation and additionally provides a scaffold for clot formation. Gelfoam® embolization provides temporary vessel occlusion, allowing recanalization in a few weeks. The temporary nature of gelatin foam occlusion can be either an advantage or disadvantage depending on the clinical situation (e.g., temporary nature is advantageous in case of hemoptysis or trauma). However, has disadvantages since it has been postulated that Gelfoam® can be associated with infection due to trapped air bubbles. Furthermore, gelatin foam powder can potentially cause ischemia due to the small size (especially at sizes<70 mm) of the particles, allowing distal embolization.
Another common embolic material is polyvinyl alcohol (PVA). Polyvinyl alcohol was first introduced as an intravascular embolization agent in 1974 in the form of a sponge, current intravascular use of polyvinyl alcohol (PVA) (available from Boston Scientific/Target Therapeutics, Cork Ltd., Cork, Ireland and Cordis J&J Endovascular, Miami, Fla.) is primarily in the form of particles. The particles are made from a PVA foam sheet that is vacuum dried and rasped into particles. The particles are filtered with sieves and are available in sizes ranging from 100 mm to 1100 mm. Polyvinyl alcohol particles provide permanent occlusion by adherence to the vessel wall, causing stagnation of flow; in addition to lodging in the smallest vessel into which they will fit. The results are an inflammatory reaction and focal angionecrosis, with vessel fibrosis developing over time. Polyvinyl alcohol particles are biocompatible, and there is vast cumulative clinical experience with PVA particle embolization. The major disadvantage of PVA particles is their tendency to aggregate, occluding vessels more proximally than might be expected based on stated size. Particle clumping can also cause catheter occlusion, which is preventable by dilution of particles, proper suspension, and slow infusion. In addition, PVA particles can accumulate in the catheter hub and theoretically cause subsequent non-target embolization when the catheter is flushed.
Another common embolic material is tris-acryl gelatin microspheres (TAGM) are useful for uterine fibroid embolization. Such materials are fabricated from an acrylic polymer matrix impregnated and embedded with porcine gelatin. They are non-resorbable hydrophilic particles that are precisely calibrated by size. In addition, tris-acryl gelatin microspheres can be temporarily compressed by 20 to 30% of their initial diameter. While embolic polyvinyl alcohol particles are known to be irregular nature, tris-acryl gelatin microspheres are smooth and spherical in shape and fragmentation is 100 not observed. Disadvantages of tris-acryl gelatin microspheres include the need for intermittent agitation to prevent sedimentation and maintain suspension. In addition, tris-acryl gelatin microspheres are partly composed of porcine gelatin, which has allergic potential.
Yet another common embolic material is ethylene vinyl alcohol copolymer (EVOH) (commercially available as Onyx®, from Micro Therapeutics, Inc., Irvine, Calif.). The material is a copolymer of ethylene and vinyl alcohol prepared with dimethyl sulfoxide (DMSO) as solvent. Tantalum powder is usually added for opacity. Upon prolonged contact with blood, the DMSO diffuses away allowing dissolution of the EVOH, which forms a solid in the blood vessel. It was has been used as an embolic since 1990 and has been used as an embolic agent for cerebral arterio-venous malformation since 2005. It has also been used for treatment of cerebral aneurysms.
Also known as an embolic agent is calcium alginate gel (available as ALGEL® from Neural Intervention Technologies, Ann Arbor, Mich.), which has been evaluated primarily for neuro-endovascular procedures. It is comprised of a polymer of alginic acid, which is a natural polysaccharide gel obtained as its water-soluble sodium salt (sodium alginate) from brown algae. When exposed to a divalent salt such as calcium chloride, the sodium alginate forms an insoluble a non-adhesive alginate gel matrix. Calcium alginate gel occlusion of AVMs and aneurysms in a swine model has been reported (Becker et al. Neurosurgery 2007; 60: 1119-1128 and Becker et al. Neurosurgery 2005; 56: 793-801).
Cyanoacrylate adhesives such as n-butyl-2 cyanoacrylate (NBCA) are well known in the art. Cyanoacrylate-based embolics have been used for various medical procedures in humans such as cerebral AVM embolization, treatment of extra-cerebral, spinal tumors, spinal AVMs and arteriovenous fistulas (AVFs), embolization of brain and spinal cord tumors, cerebral AVMs, and brain and spinal cord dural AVFs. Medical grades of n-butyl-2 cyanoacrylate are available (TruFill® from Cordis, Miami Lakes, F.L. and as Glubran® from Gem, Viareggio, Lucca, Italy). Also know are cyanoacrylate embolic agents comprising 2-hexyl-cyanoacrylate combined with an esterified fatty acid to retard polymerization and gold particles to provide radiopacity (U.S. Pat. No. 6,037,366; RE39,150; 6,476,070; 6,538,026; RE42,377 and 6,476,069). Such cyanoacrylate adhesives are generally supplied as a monomer, which is clear and free flowing liquid, which polymerizes upon contact with an aqueous environment such as blood or water. The rate of polymerization is largely dependent on the pH of the aqueous system to which it is exposed. Tantalum powder is often incorporated to provide radiographic opacification, but is also known to retard the initiation of polymerization. Disadvantages of cyanoacrylate-based embolics include acute inflammatory reaction in the vessel wall, which progresses to chronic inflammation and fibrosis or recanalization if only partial embolization is achieved.
In traditional drug delivery systems, such as oral ingestion or intravascular injection, the bioactive agent is distributed throughout the body through the systemic blood circulation and therefore, for most therapeutic agents only a small portion of the medication reaches the desired site. Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues. Bioactive agent filled polymers (both biodegradable and non-biodegradable) are used in the form of particles, microspheres, stents, implantable devices, films, foams, coatings and the like to provide a time related gradual release profile of the bioactive agent.
Therefore a need exists for improved embolic compositions and devices which have no adverse effects on surrounding normal tissue and which do not exhibit carcinogenic or teratogenic potential. A further need exists for embolic compositions that can be rapidly administered. Another need exists for embolic compositions that are also useful for the incorporation and subsequent controlled release of bioactive substances within a mammalian body and a still further need exists for controlled release of bioactive substances from solid implants formed in situ at a desired site in a mammalian body.